Monoclonal antibody technology is among the most notable scientific advances in the last quarter century. Rapid translation of this research has prolonged the survival of thousands of patients with cancer. The first approved monoclonal antibody, rituximab, a murine-human chimeric IgG1 antibody against CD20, has become standard of care for patients with B cell lymphomas. Monoclonal antibodies against HER2 (trastuzumab) and the EGF receptor (cetuximab) have similarly changed the natural history of select patients with breast cancer, and both colorectal and head and neck cancers, respectively.
Despite the promising activity of monoclonal antibodies, the response rates among patients with either refractory or advanced cancer are suboptimal typically at less than 25%. Efforts to enhance the activity of monoclonal antibodies have focused on various combinations with cytotoxic chemotherapy. This largely ignores and may partially antagonize the immunologic mechanism by which monoclonal antibodies function.
Both adaptive and innate immune cells participate in the surveillance and the elimination of tumor cells. Among the innate cells are natural killer cells (NK cells), which constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses. The cells kill by releasing small cytoplasmic granules of proteins called perforin and granzyme that cause the target cell to die by apoptosis.
Natural killer cell activity is tightly regulated, and requires an activating signal. For example, activation of the Fc receptor by antibodies allows NK cells to lyse cells through antibody-dependent cellular cytotoxicity (ADCC). Upon activation, the NK cell releases granules containing granzymes and perforin. Perforin forms pores in the cell membrane of the target cell, through which the granzymes and associated molecules can enter, inducing apoptosis.
ADCC is a primary mechanism by which tumor directed monoclonal antibody therapy works. However, conventional cytotoxic chemotherapies induce myelosuppression, decreasing the population of NK cells, thereby reducing the efficacy of ADCC. In contrast, therapies which augment NK cell function might offer the ability to improve activity of monoclonal antibodies without increasing toxicity to non-cancer cells. Clinically this is significant as an increasing population of cancer patients either due to older age, advanced disease, or prior therapies, are not candidates for conventional cytotoxic chemotherapy. The present invention addresses this issue.